A number of α,β-unsaturated ketones display cytotoxic and anticancer properties (Dimmock et al, Curr. Med. Chem. 1999, 6, 1125-1149; Dimmock et al, J. Med Chem 1999, 42, 1358-1366) and are believed to interact with cellular thiols with little or no affinity for hydroxyl and amino groups in nucleic acids (Mutus et al, Anal Biochem, 1989, 177, 237-243; Baluja et al Chem Ind. 1964, 2053-2054). This characteristic provides the potential to develop these compounds as cytotoxics, bereft of the genotoxic properties present in certain antineoplastic agents (Bevenuto et al, J. Pharm. Sci. 1993, 82, 988-991). The Mannich base form of such compounds has been investigated. For instance, Mannich bases of some conjugated enones have been shown to lead to significant increase in both the rate of thiolation and alkylation (Dimmock et al, Can J. Chem 1980, 58, 984-991) and cytotoxicity (Dimmock et al, J Pharm Sci 1975, 64, 241-249). However, compounds, such as the conjugated arylidene ketone of Formula (A) shown below, are toxic to mice.

R1=R2=H, Cl, NO2, N(CH3)2, alkoxy or alkyl;
R3=H or alkyl
Related cyclic analogues of Formula (B), shown above, have been prepared to reduce the toxicity of compounds of Formula (A).
Compound B1 (Formula B with R1=R2=H) is a cyclic Mannich base of a dienone and possesses cytotoxic activity towards the murine lymphocytic leukemia P388/MRI cell line and does bind to a synthetic DNA, poly(d(AT)); more surprisingly, five consecutive daily doses of 240 mg/kg did not induce fatalities in mice (Dimmock et al., Drug Des Delivery 1990, 6, 183-194).
Various N-substituted derivatives of compound B1 have been prepared and tested: N-3-carboxy-2-propenoyl derivatives of compound B1 were evaluated against P388/MRI cells (Dimmock et al, Drug Des. Deliv. 1990, 6, 183-194). N-Acyl derivatives (Dimmock et al, Drug Des Discovery 1992, 10, 291-299), N-amidic, and N-carbamate derivatives (Dimmock et al, Drug. Des. Discovery 1994, 12, 19-28) of compound B1 were screened against murine L1210 cells and a panel of human tumours. N-acryloyl amides (Dimmock et al, J. Med. Chem 2001, 44, 586-593), N-amidic derivatives (shown as Formula C below) (Dimmock et al. Eur J. Med. Chem., 2002, 37, 961-972), and N-maleamoyl derivatives (Dimmock et al, J. Enz. Inhib. Med. Chem., 2003, 18, 325-332) of compound B1 were evaluated against murine P388 and L1210, human Molt 4/C8 and CEM T-lymphocytes.

Compounds of Formula C have been shown to inhibit human N-myristoyltransferase and fyn kinase.
Nearly 50 percent of human cancers are either completely resistant to chemotherapy or respond only transiently, after which they are no longer affected by commonly used anticancer drugs. This phenomenon is referred to as multidrug resistance (MDR) and is inherently expressed by some tumour types while others acquire MDR after exposure to chemotherapy treatment. The ability of a therapeutic to dampen or eliminate MDR in a cell is thus an important consideration.